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MIMM 465 Final Study Guide.docx

58 Pages

Microbiology and Immun (Sci)
Course Code
MIMM 465

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MIMM 465 Final Study Guide All Material Starting After the Midterm HELICOBACTER PYLORIDr Le Moual HistoryIt has been isolated in 1983 by Barry Marshall and J Robin Warren Australian o In 1984 they identified curved bacilli in the stomach of patients with gastritis and peptic ulcerationOriginally the organism was named Campylobacter pylori because of its structural similarity to other Campylobacter species such as C jejuni curved shapedIn 1989 it was finally named Helicobacter pylori based on genetic evidences 16S RNAThis has changed completely the way that gastritis and gastric ulcers are treated use of antibiotics o Two antibiotics and a protein pump inhibitor o Originally they would have used surgery as a therapyThe scientists won the Nobel Prize in Physiology or Medicine in 2005 Helicobacter pyloriGram negativeMotile 47 flagella at one pole o Flagella as well as curved shape are very important for infectionCurved rod 23 micrometers in lengthMicroaerophilic oxygen is required but at levels that are lower than the level in the atmosphereThey produce ureaseThey care considered to be extracellular pathogens A unique nicheObligate bacterial pathogen of the human stomach cannot grow in nature or in other animalsTextbooks used to say that the environment of the stomach is too harsh to support microbial life but there are other bacteria that live in the stomach as wellIn fact H pylori lives in the mucous layer that overlays the gastric mucosaThe thick layer of mucous maintains a pH gradient from pH2 in the gastric lumen to pH7 above the epithelium Localization of H pylori in the stomach mucosaH pylori will take advantage of its curved shape and flagella to move across the mucous layerIt produces a mucinase that degrades mucous and reduces viscosityIt will colonize by adhering both to mucous and to epithelial cells where pH is close to neutralityThe animal model for this bacteria is the Mongolian Gerbil o Study foundNone in the lumen with the concentration of bacteria increasing as you move towards the epithelial layer There are about 23 layers of cells on the epithelial layer H pylori EpidemiologyPresent in the stomachs of of the worlds populationTransmission is from person to personOraloral transmission usually from parents to children via infected salivaIt is usually acquired in childhood and persists for the hosts lifetime unless treatedThis is a chronic bacterial infection and produces very little inflammationo This is important and very different from Salmonella for example Because of this this bacteria can live for a very long timeDiseases associated with H pylori o Gastritis inflammation of the gastric mucosa o Gastric ulcer defect in the gastric mucosa o Gastric adenocarcinomas gastric tumor derived from epithelial cells o Mucosaassociated lymphoid tissue MALT lymphomasIt is estimated that 1020 of infected individuals will develop gastritis andor gastric ulcersOnly 014 of infected individuals will develop gastric adenocarcinomas or lymphomasWhy do most carriers never develop gastric cancer o Cancer risk is probably related to several factorsHost polymorphism eg mutation TP53 promotes high expression of IL1beta mutations in Nod1 and Nod2 genesThese mutations are related to innate immunity and are associated with gastric cancerH pylori genetic diversity eg presence of vacA gene and cag pathogenicity islandThere are different strains depending on what part of the world that they came from o EXPERIMENTTook WT strains of H pylori and infected Mongolian Gerbils and they also took strains in which the gene coding for vacA is mutated as well as a strain that didnt contain the cag pathogenicity island These are supposed to be the two main virulence factors of the bacteria With the vacA mutant pathogenicity is pretty much the same with only some decreases But the cag mutant was very different from the WT except for the case of mild gastritis which never changed Therefore cag is an important virulence factor responsible for the severe forms of the diseases caused by the bacteria Virulence factors for colonization of the gastric mucosaImportant for binding and colonization and LPS is the one responsible for the absence of an immune responseMotility and Chemotaxis o Motility is essential nonmotile mutants cannot colonize the stomachAway from their niche the bacteria can only survive in the lumen for a few hours o Propelled by its flagella the curvedshaped H pylori travels across the viscous mucous later like a corkscrew o The movement of H pylori towards the stomach mucosa is facilitated by chemotactic factors which include arginine and bicarbonate ionsThese are secreted by the stomach mucosa and are sensed by receptors on the surface of the bacteria and signals will be sent to the flagella of the bacteria for them to rotateTherefore it moves towards the highest concentration of chemoattractant and at this point it will colonize the epithelial layer o Flagella are assembled from 2 flagellin proteins FlaA majority of the filament and FlaB located proximal to the hook o Flagellins of H pylori are glycosylated with the carbohydrate pseudaminic acid o Evasion of the Innate Immune System FlagellinH pylori flagellins FlaA and FlaB poorly stimulate human gastric epithelial cells via TLR5Purified flagellin preparations 1 microgram from various H pylori strains did not significantly stimulate the release of IL8 from human gastric epithelial cells in comparison to serovar Typhimurium FliC 100 ngIL8 release was used as a measure of inflammationTherefore Hpylori cannot trigger inflammation because they cannot activate TLR5Limited inflammation is consistent with a chronic and persistent infectionThis will only be background inflammation and will not attract neutrophilsUrease o Urease is essential for colonization and it allows survival under acidic conditions ie the lumen o Urease is an abundant cytosolic protein o Urease is an Ni2containing enzyme Ni is essential for activity that hydrolyzes urea into NH3 and CO2 o Urea is taken up by H pylori through a protongated channel UreI that opens at pH levels less than 65 o Ammonia generated diffuses into the periplasm It buffers the cytosol and periplasm and creates a neutral layer around the bacterial surface and allows the bacterium to survive for a few hoursAdhesins o Adhesion to host cellsH pylori cells adhere strongly to mucins and gastric epithelial cellsAbsence of fimbrial adhesinsBinding is mediated by several afimbrial adhesins single proteins that are known as autotransportersThe protein afimbrial adhesins is synthesized transported into the periplasm inserts into the OM and the passenger domain goes through the channel and interacts with the Lewis B and Lewis X antigens There are 23 adhesins BabA Lewis B SabA Lewis X and OipA OipA binds to an unidentified ligandCognate host receptors are sialylated glycolipids and fucosylated glycoproteins LPS o Evasion of the Innate Immune System LPSThe major Lipid A species of H pylori is tetraacylated
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